Urea derivatives as kinase modulators

• US 20050165024A1
• Filed: 11/15/2004
• Published: 07/28/2005
• Est. Priority Date: 11/13/2003
• Status: Active Grant

• Current Assignee: Ambit Biosciences Corporation (Daiichi Sankyo Company Limited)
• Original Assignee: Ambit Biosciences Corporation (Daiichi Sankyo Company Limited)
• Inventors: Patel, Hitesh K., Lockhart, David J., Lai, Andiliy G., Milanov, Zdravko V., Mehta, Shamal A., Grotzfeld, Robert M.
• Granted Patent: US 7,750,160 B2
• Time in Patent Office: Days
• US Class Current: 514/248
• CPC Class Codes: A61K 31/42 Oxazoles
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/40 Acylated on said nitrogen atom
• CPC Class Codes: C07D 261/08 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 261/14 Nitrogen atoms
• CPC Class Codes: C07D 261/18 Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
• CPC Class Codes: C07D 277/46 by carboxylic acids, or sulfur or nitrogen analogues thereof
• CPC Class Codes: C07D 277/82 Nitrogen atoms
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 471/06 : Peri-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention provides methods and compositions for treating conditions mediated by various kinases wherein derivatives of urea compounds are employed. The invention also provides methods of using the compounds and/or compositions in the treatment of a variety of diseases and unwanted conditions in subjects.

Claims

1. A compound corresponding to Formula (IB):

2. The compound of claim 1, corresponding to Formula (I):

3. The compound of claim 1, corresponding to Formula (II):

4. The compound of claim 3, corresponding to Formula (III):

5. The compound of claim 4, corresponding to Formula (IV):

6. The compound of claim 5, wherein T corresponds to Formula (V):

7. The compound of claim 6, corresponding to Formula (VI):

8. The compound of claim 7, wherein L is —

C(O)NH—

.

9. The compound of claim 8, wherein B is substituted or unsubstituted phenylene, pyridinylene, pyrimidinylene, pyridazinylene, thiophenylene, imidazolylene, or pyrrolylene.

10. The compound of claim 9, selected from the group consisting of:

11. The compound of claim 7, wherein L is —

NH—

.

12. The compound of claim 11, wherein B is substituted or unsubstituted phenylene, pyridinylene, pyrimidinylene, pyridazinylene, thiophenylene, or imidazolylene.

13. The compound of claim 12, selected from the group consisting of:

14. The compound of claim 5, corresponding to:

15. The compound of claim 5, corresponding to Formula (VII):

16. The compound of claim 15, corresponding to Formula (VIII):

17. The compound of claim 16, wherein L is a covalent bond, —

C(O)NH—

, —

OCH₂—

, or —

OCH₂CH₂—

.

18. The compound of claim 16, wherein

19. The compound of claim 18 selected from the group consisting of:

20. The compound of claim 5, corresponding to Formula (IX):

21. The compound of claim 20, corresponding to Formula (X):

22. The compound of claim 21, wherein L is a linker selected from the group consisting of a covalent bond, -(substituted or unsubstituted alkylene), —

NHC(O)—

, —

C(O)NH(substituted or unsubstituted alkylene), —

NHC(O)(substituted or unsubstituted alkylene), —

C(O)NH(substituted or unsubstituted alkenylene), —

NHC(O)(substituted or unsubstituted alkenylene)-, and —

O(substituted or unsubstituted alkylene)-.

23. The compound of claim 22, corresponding to Formula (XI):

24. The compound of claim 23, selected from the group consisting of:

25. The compound of claim 21, corresponding to Formula (XII):

26. The compound of claim 25, corresponding to:

27. The compound of claim 21, corresponding to Formula (XIII):

28. The compound of claim 27, corresponding to:

29. The compound of claim 21, corresponding to Formula (XIV):

30. The compound of claim 29, selected from the group consisting of:

31. The compound of claim 21, corresponding to Formula (XV):

32. The compound of claim 31, corresponding to:

33. The compound of claim 21, corresponding to Formula (XVI):

34. The compound of claim 33, wherein L is a linker selected from the group consisting of —

NHC(O)—

, —

OCH₂—

, —

OCH₂CH₂—

, —

NHC(O)CH₂SCH₂C(O)NH—

, —

CHCHC(O)NH—

, —

CHCHCH₂O—

, —

CH₂CH₂—

, and —

CH₂CH₂C(O)NH—

.

35. The compound of claim 34, selected from the group consisting of:

36. The compound of claim 3, corresponding to:

37. The compound of claim 5, corresponding to:

38. The compound of claim 5, corresponding to Formula (XVII):

39. The compound of claim 5, corresponding to Formula (XVIII):

40. The compound of claim 39, corresponding to Formula (XIX):

41. The compound of claim 40, wherein LI is a bond;

and L is a bond or —

C(O)NH—

.

42. The compound of claim 41, wherein U is substituted or unsubstituted phenyl, thiazolyl, or pyridinyl;

and V is substituted or unsubstituted piperidinylene, thiazolylene, imidazolylene, or thiophenylene.

43. The compound of claim 42, selected from the group consisting of;

44. The compound of claim 40, corresponding to Formula (XX):

45. The compound of claim 44, wherein L_{is a bond, —}

CH₂O—

, —

N(CH₃)—

, or —

O—

; and

L is —

CH₂O—

or —

NHC(O)—

.

46. The compound of claim 45, wherein U is substituted or unsubstituted phenyl, C₃-C₆ cycloalkyl, pyrimidine, or pyridine.

47. The compound of claim 46, selected from the group consisting of:

48. The compound of claim 40, corresponding to Formula (XXI):

49. The compound of claim 48, wherein LI is a —

NH—

or —

O—

; and

L is —

NHC(O)—

.

50. The compound of claim 49, wherein U is substituted or unsubstituted pyrmidyl.

51. The compound of claim 50, selected from the group consisting of:

52. The compound of claim 40, corresponding to:

53. The compound of claim 5, corresponding to Formula (XXII):

54. A method of modulating p38 kinase, said method comprising administering an effective amount of a compound corresponding to Formula (IA)

55. The method of claim 54, wherein said compound corresponds to Formula (I):

56. The method of claim 54, wherein said compound corresponds to Formula (IV):

57. The method of claim 56, wherein said compound corresponds to Formula (VI):

58. The method of claim 57, wherein L of said compound is —

NH—

or —

C(O)NH—

.

59. The method of claim 58, wherein B of said compound is substituted or unsubstituted phenylene, pyridinylene, pyrimidinylene, pyridazinylene, thiophenylene, or imidazolylene.

60. The method of claim 59, wherein said compound is selected from the group consisting of:

61. The method of claim 54, wherein said compound is selected from the group consisting of:

62. The method of claim 55, wherein said compound corresponds to (XXIII):

63. The method of claim 54, wherein said compound is selected from the group consisting of:

64. A method of modulating MKNK2 kinase, said method comprising administering an effective amount of a compound corresponding to Formula (IA):

65. The method of claim 64, wherein said compound corresponds to Formula (I):

66. The method of claim 65, wherein said compound corresponds to Formula (IV):

67. The method of claim 66, wherein said compound corresponds to Formula (VI):

68. The method of claim 67, wherein B of said compound is substituted or unsubstituted phenylene, pyridinylene, pyrimidinylene, pyridazinylene, thiophenylene, or imidazolylene.

69. The method of claim 68, wherein said compound is selected from the group consisting of:

70. The method of claim 66, wherein said compound corresponds to Formula (XVII):

71. The method of claim 70, wherein said compound corresponds to Formula (X):

72. The method of claim 71, wherein L of said compound is —

NHC(O)—

.

73. The method of claim 70, wherein said compound is selected from the group consisting of:

74. The method of claim 66, wherein said compound is selected from the group consisting of:

75. A method of modulating STK10 kinase, said method comprising administering an effective amount of a compound corresponding to Formula (IA):

76. The method of claim 75, wherein said compound corresponds to Formula (I):

77. The method of claim 76, wherein said compound corresponds to Formula (IV):

78. The method of claim 77, wherein said compound corresponds to Formula (VI):

79. The method of claim 78 wherein L of said compound is —

NH—

or a covalent bond.

80. The method of claim 79, wherein B of said compound is substituted or unsubstituted phenylene, pyridinylene, pyrimidinylene, pyridazinylene, thiophenylene, or imidazolylene.

81. The method of claim 80, wherein said compound is selected from the group consisting of:

82. A method of treating a cellular proliferative disorder, said method comprising administering a therapeutically effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to Formula (IA)

83. The method of claim 82, wherein said compound corresponds to Formula (IB):

84. The method of claim 83, wherein said compound corresponds to Formula (I):

85. The method of claim 84, wherein said compound corresponds to Formula (II):

86. The method of claim 85, wherein said compound corresponds to Formula (III):